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Fast 3D molecular superposition and similarity search in databases of flexible molecules

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Abstract

We present a new method (fFLASH) for the virtual screening of compound databases that is based on explicit three-dimensional molecular superpositions. fFLASH takes the torsional flexibility of the database molecules fully into account, and can deal with an arbitrary number of conformation-dependent molecular features. The method utilizes a fragmentation-reassembly approach which allows for an efficient sampling of the conformational space. A fast clique-based pattern matching algorithm generates alignments of pairs of adjacent molecular fragments on the rigid query molecule that are subsequently reassembled to complete database molecules. Using conventional molecular features (hydrogen bond donors and acceptors, charges, and hydrophobic groups) we show that fFLASH is able to rapidly produce accurate alignments of medium-sized drug-like molecules. Experiments with a test database containing a diverse set of 1780 drug-like molecules (including all conformers) have shown that average query processing times of the order of 0.1 seconds per molecule can be achieved on a PC.

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References

  1. Matter, H. and Rarey., M., In Jung, G. (Ed.) Combinatorial Organic Chemistry. John Wiley & Sons, New York, NY, 1999.

    Google Scholar 

  2. Humblet, C. and Dunbar Jr., J.B., In Venuti, M.C. (Ed.) Annual Reports in Medicinal Chemistry. Vol. 28, Chapter VI. Topics in Drug Design and Discovery. Academic Press, London, 1993, pp. 275-284.

    Google Scholar 

  3. Willet, P., J. Mol. Recognition, 8 (1995) 290.

    Google Scholar 

  4. Brown, R.D. and Martin, Y.C., J. Chem. Inf. Comput. Sci., 36 (1996) 572.

    Google Scholar 

  5. Klebe, G., Mietzner, T., and Weber, F., J. Comput. Aided Mol. Des., 8 (1994) 751.

    Google Scholar 

  6. Kearsley, S.K. and Smith, G.M., J. Comput. Aided Mol. Des., 8 (1994) 565.

    Google Scholar 

  7. Klebe, G., Mietzner, T., and Weber, F., J. Comput. Aided Mol. Des., 13 (1999) 35.

    Google Scholar 

  8. Lemmen, C., and Lengauer, T., J. Comput. Aided Mol. Des., 11 (1997) 357.

    Google Scholar 

  9. Lemmen, C., Lengauer, T., and Klebe, G., J. Med. Chem., 41 (1998) 4502.

    Google Scholar 

  10. Lemmen, C., Hiller, C., and Lengauer, T., J. Comput. Aided Mol. Des., 12 (1998) 491.

    Google Scholar 

  11. Miller, M.D., Sheridan, R.P., and Kearsley, S.K., J. Med. Chem., 42 (1999), 1505.

    Google Scholar 

  12. Grant, J.A., Gallardo, M.A., Pickup, B.T., J. Comput. Chem., 17 (1996) 1653.

    Google Scholar 

  13. McMartin, C. and Bohacek, R.S., J. Med. Chem., 42 (1999) 1505.

    Google Scholar 

  14. Handschuh, S., Wagener, M. and Gasteiger, J., J. Chem. Inf. Comput. Sci., 38 (1998) 220.

    Google Scholar 

  15. Lemmen, C., and Lengauer, T., J. Comput. Aided Mol. Des., 14 (2000) 215.

    Google Scholar 

  16. Lemmen, C., Zimmermann, M., and Lengauer, T., Perspectives in Drug Discovery and Design, 20 (2000) 43.

    Google Scholar 

  17. Kearsley, S.K, J. Comput. Chem., 11 (1990) 1187.

    Google Scholar 

  18. Diamond, R., Protein Sci., 1 (1992) 1279.

    Google Scholar 

  19. Mestres, J., Maggiora, G.M. and Rohrer, D.C., J. Mol. Graph., 15 (1997) 114.

    Google Scholar 

  20. Cosgrove, D.A., Bayada, D.M. and Johnson, A.P., J. Comput. Aided Mol. Des., 14 (2000) 573.

    Google Scholar 

  21. Labute, P., William, C., Feher, M., Sourial, E. and Schmidt, J.M., J. Med. Chem. 44 (2001) 1483.

    Google Scholar 

  22. Mills, J.E.J., de Esch, I.J.P., Perkins, T.D.J. and Dean, P.M., J. Comput. Aided Mol. Des., 15 (2001) 81.

    Google Scholar 

  23. Roberts, G.C.K., Drug Discovery Today, 5 (2000) 230.

    Google Scholar 

  24. Pitman, M.C., Huber, W.K., Horn, H., Krämer, A., Rice, J.E. and Swope, W.C., J. Comput. Aided Mol. Des., 15 (2001) 587.

    Google Scholar 

  25. Lawton, J., Tudor, M. and Wipke, W.T., In Parrill, A.L. and Reddy, M.R. (Eds.) Rational Drug Design: Novel Methodology and Practical Applications. ACS Symposium Series 719, Oxford University Press, 1999, pp. 239-254.

  26. FlexS-77 dataset collected by C. Lemmen, G. Klebe, M. Böhm, first published in [9] (http://www.biosolveit.de)

  27. Compounds 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 21, 22, 23, 24, 25, 29, 30, 31, 32, 34, 35, 36, 38, 39, 41, 42, 43, 45, 46, 47, 48, 50, 52, 54, 56, 57, 60, 62, 63, 64, 65, 66 from Crippen, G.M., J. Med. Chem. 23 (1980) 599.

    Google Scholar 

  28. The NCI diversity set can be found at http://dtp.nci.nih.gov/docs/3d database/structural information /structural data.html.

  29. Carbo, R., Leyda, L. and Arnaua, M., Int. J. Quant. Chem., 17 (1980) 1185. In the present work the Carbo function is used with three-dimensional Gaussian densities exp\({\text{(}} - (\vec r - \vec r_0 )^2 /2\tau ^2 )\), where \(\vec r_0 \) is an atom center and ? = 1 Å [24].

    Google Scholar 

  30. See e.g. in Chartrand, G., Introductory Graph Theory, Dover, 1985.

  31. See e.g. in Sedgewick, R.,Algorithms in C++, Addison-Wesley, New York, 1992.

    Google Scholar 

  32. Pardalos, P.M., University of Florida, 1997.

  33. Clark, M., Cramer III, R.D. and Van Opdenbosch, N., J. Comput. Chem. 10 (1989) 982.

    Google Scholar 

  34. Bondi, A., J.Phys.Chem., 68 (1964) 441.

    Google Scholar 

  35. Mason, J.S., Morize, I., Menard, P.R., Cheney, D.L., Hulme, C. and Labau-diniere, R.F., J. Med. Chem. 42 (1999) 3251.

    Google Scholar 

  36. Eksterowicz, J.E., Evensen, E., Lemmen, C., Brady, G.P., Lanctot, J.K., Bradley, E.K., Saiah, E., Robinson, L.A., Grootenhuis, P.D.J. and Blaney, J.M., J. Mol. Graphics Modelling 20 (2002) 469.

    Google Scholar 

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Krämer, A., Horn, H.W. & Rice, J.E. Fast 3D molecular superposition and similarity search in databases of flexible molecules. J Comput Aided Mol Des 17, 13–38 (2003). https://doi.org/10.1023/A:1024503712135

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